The Glycine Receptor in a Rat Tinnitus Model: A Possible Therapeutic Target

大鼠耳鸣模型中的甘氨酸受体：可能的治疗靶点

• 批准号: 7371960
• 负责人: Donald M. Caspary
• 金额: $ 30.31万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371960
• 关键词: Affinity; Age; Aging; Animal Model; Animals; Appearance; Auditory; Auditory system; Autoradiography; Behavioral; Binding; Brain-Derived Neurotrophic Factor; Cell surface; Chronic; Cochlea; Condition; Deafferentation procedure; Detection; Development; Dose; Elderly; Electrodes; Esthesia; Event; Frequencies; Functional disorder; Fusiform Cell; Generations; Glycine; Glycine Receptor Binding; Glycine Receptors; Hyperactive behavior; In Situ Hybridization; Incidence; Label; Laboratories; Lead; Link; Longevity; Measures; Modeling; Molecular; Nerve Growth Factor Receptors; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Noise; Numbers; Output; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Plastics; Population; Property; Protein Subunits; Proteins; Quality of life; Radiolabeled; Range; Rate; Rattus; Research Personnel; Role; Scaffolding Protein; Series; Structure; Strychnine; Surgical Disarticulation; Testing; Therapeutic; Thinking; Tinnitus; Trauma; Western Blotting; Work; age related; aged; dorsal cochlear nucleus; experience; gephyrin; immunocytochemistry; insight; juvenile animal; neurochemistry; neurotransmission; neurotrophic factor; novel; programs; radiotracer; receptor; receptor binding; receptor sensitivity; relating to nervous system; response; sensory system; sound; therapeutic target; young adult

DESCRIPTION (provided by applicant): Chronic tinnitus is a phantom auditory sensation experienced by up to 15% of the population. Between 2 and 10% of the tinnitus population typically experience a continuous high frequency ringing or hiss sufficiently loud to impact severely on their quality of life (Cooper, 1994). Tinnitus has been found to increase with aging. Thus, the incidence of tinnitus is likely to increase due to increased longevity and recreational noise exposure. Much of the present thinking regarding the generation of tinnitus revolves around the appearance of spontaneous activity and neural hyperactivity in certain central auditory structures. A working hypothesis which parallels findings in other sensory systems suggests that partial deafferentation leads to central changes, generally involving altered inhibitory neurotransmission. Partial peripheral auditory deafferentation may produce tinnitus, coincident with a selective loss of inhibitory glycinergic function in the dorsal cochlear nucleus (DCN). Proposed studies will examine the functional and molecular neurochemical impact of aging in rats with behavioral evidence of tinnitus. Preliminary results find age and noise-exposure related changes in glycine receptor and neurotrophic factor neurochemistry in DCN of rats with behavioral evidence of tinnitus. Proposed studies will compare functional and molecular neurochemical changes between young and aged controls, and young and aged sound-exposed rats with behavioral evidence of tinnitus. Specifically: 1) quantitative measures of message and protein will be used to examine changes in the subunit make up of the glycine receptor, the scaffolding protein, gephyrin, and the protective neurotrophin BDNF; 2) recordings from DCN fusiform cells will parallel behavioral studies/gap detection and examine inhibitory response properties and glycine receptor sensitivity and 3) quantitative receptor binding will be used to examine changes in glycine and neurotrophin receptor pharmacology. Findings from these studies will provide new information regarding tinnitus-related changes in glycine neurotransmission and possible neurotrophin protection in an animal model of tinnitus. Understanding the impact of aging on tinnitus-related changes in neurochemistry related to glycine and the BDNF receptor (TrkB) function might help define unique targets for the development and testing of novel selective drugs for the treatment of tinnitus.

描述（由申请人提供）：慢性耳鸣是一种虚幻的听觉感觉，高达15%的人口经历过。2%到10%的耳鸣患者通常会经历持续的高频铃声或嘶嘶声，足以严重影响他们的生活质量（Cooper, 1994）。人们发现耳鸣会随着年龄的增长而增加。因此，耳鸣的发病率很可能由于寿命的延长和娱乐性噪音的暴露而增加。目前关于耳鸣产生的许多想法围绕着某些中央听觉结构的自发活动和神经过度活跃的出现。一个与其他感觉系统的发现相似的工作假设表明，部分传入神经丢失导致中枢改变，通常涉及抑制性神经传递的改变。部分外周听觉传入障碍可引起耳鸣，同时伴有耳蜗背核（DCN）抑制性甘氨酸能功能的选择性丧失。拟议的研究将检查老化对耳鸣行为证据大鼠的功能和分子神经化学影响。初步结果发现有耳鸣行为证据的大鼠DCN中甘氨酸受体和神经营养因子神经化学的变化与年龄和噪声暴露有关。拟议的研究将比较年轻和老年对照以及年轻和老年声音暴露大鼠与耳鸣行为证据之间的功能和分子神经化学变化。具体来说：1)信息和蛋白质的定量测量将用于检测甘氨酸受体、支架蛋白、格菲林和保护性神经营养因子BDNF组成亚基的变化；2) DCN梭状细胞的记录将与行为研究/间隙检测平行，并检查抑制反应特性和甘氨酸受体敏感性；3)定量受体结合将用于检查甘氨酸和神经营养因子受体药理学的变化。这些研究结果将为耳鸣动物模型中甘氨酸神经传递的变化和可能的神经营养因子保护提供新的信息。了解衰老对耳鸣相关的甘氨酸和BDNF受体（TrkB）功能相关神经化学变化的影响，可能有助于为开发和测试治疗耳鸣的新型选择性药物确定独特的靶点。